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Rheumatology and Orthopedic Medicine
Review Article ISSN: 2399-7370
The importance of vitamin D
Maritza Vidal Wilman1* and Nancy E Lane2
Centro de Diagnóstico de Osteoporosis y Enfermedades Reumáticas (CEDOR) Lima, Perú
1
Center for Musculoskeletal Health, University of California at Davis School of Medicine, Sacramento, California, 95817, USA
2
Abstract
Vitamin D fulfills various functions in bone and mineral metabolism through its action on three main organs: the intestine, kidney, and bones. Calcitriol
[1,25-(OH)2-D3] is the metabolically active form of vitamin D and has a high affinity for its receptor (VDR), which is expressed in most cell types. This union allows
it to perform its functions at the skeletal and extra-skeletal level. Prolonged deficiency of this vitamin is mainly associated with alterations in bone mineralization and
a decrease in bone mineral density leading to the subsequent development of osteomalacia and osteoporosis. This article will review the metabolism of vitamin D, its
actions at the musculoskeletal level and the consequences of the deficiency, as well as the necessary guidelines to establish the diagnosis and adequate treatment of
supplementation.
Introduction Cholecalciferol is transported bound to vitamin D transport protein
to the liver, where it undergoes a hydroxylation in position 25, forming
Vitamin D is fat-soluble molecule and has a structure very similar the 25-(OH)-D3 (calcidiol), mainly by action of several cytochrome P450
to cholesterol; it is essential in maintaining bone mass and mineral enzymes (CYP2R1, CYP27A1), named as vitamin D3-25-hydroxylase
metabolism. Vitamin D acts similarly to steroid hormones, modulating [10,11]. This form of vitamin D is inactive, but due to its stability and
the bone metabolism at a distance and directing, and interacting with greater solubility in water, it represents the major circulating metabolite
other hormones. Vitamin D even acts locally as a cytokine, contributing and vitamin D deposit [2]. The useful life of this metabolite is about
to an immune response, cellular differentiation and proliferation ≈ 10-19 days and the circulating calcidiol pool is in balance with that
suggesting the extra-skeletal effects of this hormone [1,2]. The functions stored in adipose tissue and muscle. For all these reasons, the serum
of vitamin D on calcium and phosphorus metabolism are through its measurement of 25-(OH)-D3 reflects the status and body storage of
effect of three main organs: intestine, bone and kidney. There are two the vitamin [12-14]. Subsequently, 25-(OH)-D3 undergoes a second
known forms of vitamin D: cholecalciferol (vitamin D3) of animal hydroxylation in the proximal tubular cells of the kidney, through the
origin, and ergocalciferol (vitamin D2) of vegetable origin and they action of 1-α-hydroxylase enzyme (CYP27B1), producing the active
share the same metabolic pathways (Table 1). The 7-dehydrocholesterol form of vitamin D known as calcitriol: 1,25-(OH)2-D3. Hydroxylation
(provitamin D3) is the steroid precursor in animals; and ergosterol in the liver is constitutive; while renal hydroxylation is highly regulated
is the precursor in plants and fungi. The 7-dehydrocholesterol forms by different factors [12,15].
vitamin D3 (cholecalciferol) while ergosterol becomes vitamin D2 Intestinal malabsorption syndromes alter the absorption of fat-
(ergocalciferol) (Figure 1) [1,3-6]. soluble components such as vitamin D; and a high proportion of
Vitamin D can be obtained from the exposition to sunlight (which vitamin D bound to proteins in urine is lost in nephrotic syndrome
constitutes the main source in humans) or from nutritional sources [16]. Obesity is associated with lower levels of physical activity and
of vitamin D-rich foods [2]. Vitamin D3 is synthesized in the skin outdoor activities that can result in less skin synthesis of vitamin D by
from 7-dehydrocholesterol (provitamin D3), which is photolyzed the sun, and vitamin D sequestration in adipose tissue [17]. Dark skin,
limited sun exposure and low intake of foods fortified with vitamin D
into pre-vitamin D3 through exposure to ultraviolet B sunlight; and it
can all contribute to vitamin D deficiency [16,18]. The 1,25-(OH)2-D3
subsequently undergoes a thermally induced transformation to vitamin
is also able to regulate its own production through inhibition of the
D3 (cholecalciferol). Cutaneous synthesis of vitamin D is influenced by
1-α-hydroxylase enzyme; and apparently, this is a very effective
factors affecting the number of photons of ultraviolet B light reaching
mechanism to inhibit the formation of this metabolite when there
the skin [7]. Melanin is a natural sunscreen and it effectively absorbs
is an adequate status of vitamin D. The enzyme 1-α-hydroxylase is
photons of ultraviolet B light, so that people with dark skin synthesize
less vitamin D; this is the main reason for the high incidence of vitamin
D deficiency in this population (Figure 2) [7,8].
Sunscreens, with sun protection factor equal to or greater than 8, *Correspondence to: Maritza Vidal Wilman, Centro de Diagnóstico de
Osteoporosis y Enfermedades Reumáticas (CEDOR) Lima-Perú, E-mail:
absorb between 92% and 95% of ultraviolet B photons, and significantly
maritzavw@gmail.com
reduce the cutaneous synthesis of vitamin D3 [9]. Age also affects the
cutaneous synthesis of vitamin D, and it is estimated that by age 70, Key words: Vitamin D, colecalciferol, calcitriol, osteoporosis, osteomalacia
the synthesis of vitamin D is only 25% of what a person of 20 years Received: March 01, 2020; Accepted: March 16, 2020; Published: March 28,
synthesizes normally [7]. 2020
Rheumatol Orthop Med, 2020 doi: 10.15761/ROM.1000171 Volume 5: 1-9Vidal M (2020) The importance of vitamin D
also expressed in other tissues outside the kidney including the skin,
intestine, brain, testicles, macrophages and placenta, which may explain
some of the extra-skeletal effects of the vitamin [19,20].
The major pathway for the inactivation of the vitamin D metabolites
is via an additional hydroxylation through a third enzyme: CYP24A1
which degrades calcidiol and calcitriol into 24-hydroxylated products
and are excreted through the bile into the feces (Figure 3) [2,4,5,19,20].
The 1,25-(OH)2-D3 is the main inducer of CYP24A1 promoting
its inactivation and, if needed, limiting its biological effects [6,21].
The polar metabolites of 1,25-(OH)2-D3 are secreted into bile and
Figure 3. Formation of inactive metabolites of vitamin D. CYP27B1:1-α-hydroxylase
reabsorbed via enterohepatic circulation. Modifications of this pathway,
enzyme; CYP24A1: 24-hydroxylase enzyme
observed in patients with terminal ileum diseases, lead to accelerated
Table 1. Terms and definitions
Chemical precursor of vitamin D3. It is converted
7-dehydrocholesterol to vitamin D3 in the skin, therefore functioning as
provitamin-D3
Steroid hormone produced in the skin when exposed to
Cholecalciferol (Vitamin D3)
ultraviolet light
Vitamin D of vegetable origin formed by the ultraviolet
Ergocalciferol (Vitamin D2)
irradiation of ergosterol
Calciferol Fat-soluble steroid, referred commonly as vitamin D
Steroid precursor in plants and fungi that becomes
Ergosterol
vitamin D2
Calcidiol [25-OH-D]
Hepatic metabolite produced after the first
[25-OH-D3] if animal origin
hydroxylation of cholecalciferol in the liver.
[25-OH-D2] if vegetable origin
Calcitriol [1,25-(OH)2-D]
[1,25-(OH)2-D3] if animal origin Active form of vitamin D
[1,25-(OH)2-D2] if vegetable origin
CYP2R1, hepatic enzyme in charge of hydroxylation of
25-hydroxylase enzyme
cholecalciferol into calcidiol
CYP27B1, renal enzyme in charge of hydroxylation of
1-α-hydroxylase enzyme
calcidiol into calcitriol
25-(OH)-D-24-α-hydroxylase CYP24A1, oxidation enzyme that catabolizes
24-hydroxylase metabolites of vitamin D into soluble calcitroic acid for
1,25-(OH)2-D-24-hydroxylase rapid renal excretion
Inactive product result of the catabolism of calcitriol, it
Calcitroic acid
is soluble in water and excreted in bile
Figure 1. Vitamin D metabolites
loss of vitamin D metabolites [19]. In the kidney, 1-α-hydroxylase
enzyme is induced by PTH, hypocalcemia and hypophosphatemia in
order to form a greater amount of 1,25-(OH)2-D3 [6,22].
The biological activity of the 1,25-(OH)2-D3 is mediated by its
high affinity to nuclear vitamin D receptor (VDR), which acts as a
transcriptional factor activated by ligand [23]. The VDR was originally
found in tissues involved in calcium metabolism such as bone, intestine,
kidney and parathyroid gland, but it is known that its distribution is
wider, which helps to explain the additional actions attributed to this
hormone [19,21].
Vitamin D3 (cholecalciferol) and vitamin D2 (ergocholesterol) are
fat-soluble vitamins, and when ingested are absorbed in the small bowel
in presence of bile salts incorporated into chylomicrons and transported
in the circulation bound to plasma proteins (mainly vitamin D binding
protein) [19,24-27]. Finally, they follow the same metabolic pathways
and enzymatic transformations above described [19,20]. Both forms
of vitamin D have qualitatively similar biologic actions and they are
stored in fat cells. Plasmatic concentration of 1,25-(OH)2-D3 is 1000
times lower than 25-(OH)-D and has a half-life of 3-6 hours. In addition,
levels of 1,25-(OH)2-D3 can be found normal or even elevated in people
with vitamin D deficiency due to secondary hyperparathyroidism [27,28].
Figure 2. Vitamin D synthesis pathway. CYP2R1: 25-hydroxylase enzyme; CYP27B1:
In the intestine, vitamin D improves the absorption of calcium
1-α-hydroxylase enzyme; CYP24A1: 24-hydroxylase enzyme and phosphorus by increasing the expression of the epithelial channels
Rheumatol Orthop Med, 2020 doi: 10.15761/ROM.1000171 Volume 5: 2-9Vidal M (2020) The importance of vitamin D
of intestinal calcium [19,24] and upregulation of calbindin D9K, a controlled study evaluated the annual administration of a high dose
calcium binding protein which is expressed in the intestine and plays of vitamin D (500,000 IU of cholecalciferol) orally in older women
an important role of active transport of calcium through the enterocyte versus the administration of placebo. The study found that 171 patients
[19,21,24]. In bone, vitamin D has effects on bone turnover, it can suffered fractures in the vitamin D group versus 135 in the placebo
increase bone resorption in order to maintain calcium homeostasis; group; individuals who received vitamin D presented 2,892 falls
but it also plays an important role in the mineralization of the bone versus 769 in the control group. The study concluded that the annual
matrix and in the development of proper bone mass [19,29]. Vitamin administration of a high dose of vitamin D was associated with a high
D can induce bone resorption through the molecular mechanism of risk of falls and fractures. Interestingly, in the vitamin D group there was
the receptor activator for nuclear factor κB ligand (RANKL) [30], a 31% higher incidence of falls in the first 3 months following dosing,
osteoblasts have receptors (VDR) that recognize 1,25-(OH)2-D3 and and 13% during the following 9 months [46]. The increase in the risk of
thus increase the expression of RANKL in its membrane [20,31,32]. falls and fractures with the use of vitamin D megadose has motivated
The osteoclastic progenitor cells have receptors (RANK) that bind extensive analysis in the literature on the possible mechanisms of
to RANKL, inducing its maturation and activity [20,31,32]. Vitamin action. Dawson-Hughes postulated that the 500 000 IU-dose may have
D effects in bone can depend on the state of the calcium balance, in triggered a “short-term protective reaction” in which CYP24 was up-
hypocalcemia it might increase osteoclastogenesis to restore the normal regulated, and consequently a decreased in blood and tissue levels of
calcium balance [20]. 1,25-(OH)2-D3 [47,48]. Some evidence suggests a U-shaped response to
vitamin D for outcomes including falls and fractures, with lowest risk at
When calcium obtained from the diet is insufficient to maintain moderate levels of serum, and increased risk at low and high vitamin D
normal serum levels of this mineral, reduced levels of ionized calcium levels [19] suggesting an increased risk in those with the highest serum
is recognized by the calcium sensor in the parathyroid gland and the 25-OH-D levels [49]. Rossini suggests that a transient increase in bone
production and release of PTH is increased. PTH promotes renal turnover markers and in bone resorption may explain the negative
production of 1,25-(OH)2-D3 and it also promotes renal calcium clinical results obtained in studies using intermittent high dose vitamin
reabsorption [33]. Moreover, PTH interacts with the osteoblastic D [50]. These observations raise the question if rapid increases in serum
PTH-1 receptor and the 1,25-(OH)2-D3 interacts with its receptor in 25-OH-D have adverse musculoskeletal effects, especially in those with
osteoblasts [20,34] resulting in an increased expression of RANKL, normal or close to normal vitamin D serum values.
which by interacting with its RANK receptor in the pre-osteoclast,
initiates the transformation and maturation from pre-osteoclasts The numerous studies conducted with vitamin D supplementation
to mature osteoclasts enhancing the bone resorption to maintain have resulted in contradictory results, making hard to reach a definitive
acceptable calcium levels in blood. Likewise, vitamin D regulates conclusion about the effect of vitamin D on muscle strength as well
transcription, differentiation and maturation of osteoblasts; and it as the risk of falls and subsequent fractures. In relation to falls, Tang
increases the synthesis of collagen and other bone matrix proteins comments that this discrepancy could be attributed to the heterogeneity
[27,35,36]. For normal mineralization, a balance between the levels of of the included clinical studies because some have not incorporated all
inorganic phosphate (Pi) and extracellular inorganic pyrophosphate the important parameters in their design to analyze this association,
(PPi) is required. This process is regulated by the PTH - 1,25-(OH)2-D3 such as the type of population studied (sufficient or deficient vitamin D
axis, and by other local and systemic factors [37]. The degree of patients), the form and dose of administration of the supplements and
bone mineralization is an important determinant of bone strength the way to collect information on falls [51].
and fracture toughness [38]. Moreover, vitamin D is involved in the
conservation of bone microarchitecture and strength [39,40].
Dietary requirement of vitamin D and blood levels
Despite the high prevalence of vitamin D deficiency, there is a
Vitamin D exerts other actions on the human musculoskeletal
debate among different societies regarding the adequate daily intake of
system, which supports the transport of calcium in the muscle, the
vitamin D as well as the definition of vitamin D deficiency. The Institute
growth of muscle cells and the synthesis of proteins necessary for
of Medicine report recommended that an adequate intake of vitamin D
good muscle function [19,41]. This action is mediated by genomic
for children under one year of age should be in the range of 400 IU per
(through VDR receptor) and non-genomic pathways. The muscle
day, the recommended dietary allowance (RDA) for children ≥1 year
strength in the quadriceps, grip strength and muscle function in the
and for adults until 70 years old should be in the range of 600 IU per
lower limbs is positively correlated to serum 25-(OH)-D [42,43]. The
day; whereas for adults over age 70 years should be in the range of 800
beneficial actions of vitamin D on muscle include a reduction in the
IU per day [19]. Some clinical guidelines and other authors recommend
risk of falls and fractures. Ninety percent of non-vertebral fractures
considering the RDA values proposed by IOM as the recommended
related to osteoporosis are associated with low impact falls; and vitamin
minimum daily intake. It is still not clear whether these values are
D supplement reduced by 49% the risk of further falls, contributing
enough to obtain the extra skeletal benefits of vitamin D [27,52,53].
significantly to reduce the risk of fractures [41]. Bischoff-Ferrari
However, these recommendations have been questioned as a daily
conducted a meta-analysis and found 22% reduction in falls (corrected
supplement intake of 600 IU of vitamin D would not be enough to
OR, 0.78, 95% confidence interval [CI], 0.64-0.92) compared to
produce levels of 25-OH-D ≥ 10 ng/ml (25 nmol/L) [53].
patients who received calcium or placebo. The investigators concluded
supplementing vitamin D might reduce the risk of falls among older The American Association of Clinical Endocrinologists for patients
people [44]. Another meta-analysis evaluated 26 clinical studies with a at risk for vitamin D deficiency recommend the intakes of 400 IU per
total of 45,782 enrolled patients. The administration of vitamin D reduced day for children under 1 year of age, and 600 IU for children 1 year
the risk of falls, especially in those who had a deficiency of vitamin D by and older to maximize bone health, but 1,000 IU per day are needed
administering with calcium supplementation (OR for suffering at least to raise the blood level of 25-(OH)-D consistently above 30 ng/ml.
one fall, 0.86, 95% confidence interval, 0.77-0.96). However, the quality In adults older than 18 years, 1,500 to 2,000 IU per day are required
of the evidence was low in this study [45]. Conversely, a randomized to achieve this same goal [27]. The recommended dietary allowance
Rheumatol Orthop Med, 2020 doi: 10.15761/ROM.1000171 Volume 5: 3-9Vidal M (2020) The importance of vitamin D
(RDA) for pregnant and breastfeeding women is 600 IU of vitamin to an increased gain of bone mass in proper conditions of calcium
D, but in order to raise the values of 25-(OH)-D over 30 ng/ml (75 ingestion [61]. This is important because in late adolescence, 25-50%
nmol/L), it is required 1,500 to 2,000 IU per day at least. Double or of the peak bone mass is reached during this period [62] so deficient
triple doses of vitamin D may be needed for obese children and adults ingestion of calcium and vitamin D has deleterious effects on the peak
at all age and for those receiving corticosteroids, anticonvulsants, bone mass that will be reached in adulthood. Vitamin D deficiency is
antifungal like ketoconazole, and medicine used in HIV treatment related to decreased bone mass in children; and with a high increase in
[27]. The measurement of 25-(OH)-D in the serum reflects the body the risk of fractures, particularly at distal radius [63,64].
reserve of this vitamin, which derives from skin synthesis and vitamin
In pregnant women, vitamin D deficiency is related to an elevated
D intake (diet and supplements). Measurement of this metabolite is an
rate of bone turnover, loss of bone mass, osteomalacia, myopathy,
acceptable indicator of its status in the human body and represents the
and an increased risk of preeclampsia and cesarean section [27,65].
test of choice to identify the sufficiency or deficiency of vitamin D [54].
Maternal vitamin D deficiency is correlated with neonatal vitamin D
It is generally considered that 25-(OH)-D values under 8-10 deficiency and can have a negative effect on fetal skeletal mineralization
ng/ml (20-25 nmol/L) induce osteomalacia; 25-(OH)-D values and development, which can result in congenital rickets, craniotabes,
between 10-16 ng/ml (25-40 nmol/L) are associated with secondary and poor bone mineral content [65,66]. Vitamin D deficiency in
hyperparathyroidism and osteoporosis, and levels above 20 ng/ml were pregnant women and its implications for the mother and fetus health
considered normal [55]. However, some investigators report that values has led some experts in this area to recommend the screening for
of at least 30 ng/ml (75 nmol/L) of 25-(OH)-D in serum are required in hypovitaminosis D in all patients in early pregnancy [65]. In the elderly,
order to maximize the beneficial effects on health [56]. The maximum low vitamin D levels along with other factors, represent the first step
reference value of 25-(OH)-D in serum is not clearly defined either, towards secondary hyperparathyroidism, which leads silently to bone
but for some authors the toxicity value begins approximately at 100 ng/ loss, especially at the cortical regions. This step may be reversed by the
ml (250 nmol/L) [57]. The IOM report defines vitamin D deficiency administration of vitamin D [67]. In this age group, in addition to the
when 25-(OH)-D values are below 20 ng/ml (50 nmol/L). This report deleterious effects on bone, consequences of vitamin D deficiency on
concludes that serum levels of 25-(OH)-D of 16 ng/ml (40 nmol/L) muscle are well known, causing muscle strength and function decrease,
meet the requirements of approximately half of the population, levels of which results in muscle weakness and poor motor coordination, which
25-(OH)-D of 20 ng/ml (50 nmol/L) meet the requirements of more than can result in falls and increased risk of fractures [68]. In the elderly,
97.5% of the population, and levels of 25-(OH)-D above 50 ng/ml (125 vitamin D deficiency is considered a risk factor for falls and fractures.
nmol/L) could be associated to adverse events [19]. Recommendations The effects of vitamin D deficiency on muscle may occur even before
for administration of vitamin D from the UK National Osteoporosis bone changes are developed [69]. An important aspect that we should
Society (NOS), also define vitamin D deficiency when values are below consider as clinicians is that osteomalacia occurs if hypovitaminosis
12 ng/ml (30 nmol/L), levels between 12 and 20 ng/ml (30 and 50 D is severe and long standing. Mild or moderate hypovitaminosis D
nmol/L) are inadequate to some people, and levels above 20 ng/ml (50 cannot produce osteomalacia, but it can contribute to the development
nmol/L) define vitamin D sufficiency for most individuals [58]. of osteoporosis and the alteration of muscular function, so most of the
consensus emphasizes the importance of early correction of the vitamin
The consensus of the American Association of Clinical
D deficiency as part of the comprehensive management of osteoporosis
Endocrinologists defines vitamin D deficiency when the values of
[70-72].
25-(OH)-D are below 20 ng/ml (50 nmol/L), insufficiency when they
are between 21-29 ng/ml (52.5-72.5 nmol/L); and sufficiency when they Finally, the efficacy of medications for osteoporosis has been
are 30 ng/ml (75 nmol/L); and the safety margin to minimize the risk demonstrated in a number of clinical studies related to calcium
of hypercalcemia is defined when the value of 25-(OH)-D is ≥100 ng/ and vitamin D; and it is considered that this vitamin maximizes the
ml (250 nmol/L) [27]. However, there is also controversy regarding the effectiveness of the drug prescribed for prevention of fractures with a
definition of vitamin D deficiency; in the recent NOF guidelines for good safety profile [73,74]. Carmel et al reported that patients with a
the management of osteoporosis, it is also recommended that optimum mean 25-(OH)-D ≥33 ng/ml (82.3 nmol/L) had a greater probability
value of 25-(OH)-D must be 30 ng/ml (75 nmol/L), otherwise it would of maintaining the bisphosphonate response [75]. For these reasons,
be classified as vitamin D deficiency [59]. it is advisable to correct the deficiency of vitamin D and to maintain
optimum levels before starting the treatment for osteoporosis.
Vitamin D deficiency and its consequences
What form of Vitamin D should we recommend, and
In past decades, studies have found 12.5% to 76% of osteoporotic
postmenopausal women with vitamin D values below 12 ng/ml, with
which route?
regional and seasonal variations; and this deficiency is accentuated The cholecalciferol and ergosterol metabolic pathways are similar,
in direct proportion to the age of studied group, influencing when either form of vitamin D is administered, they transform initially
negatively to bone metabolism [60]. In states of vitamin D deficiency, in 25-(OH)-D, and then in 1,25-(OH)2-D. 1,25-(OH)2-D3 controls
decreased calcium absorption in the intestine causes secondary its own synthesis due to feedback regulation mechanisms [4,76] so,
hyperparathyroidism, resulting in bone loss. In addition, loss of renal when cholecalciferol or ergocalciferol is administered, even in supra-
phosphate alters the calcium-phosphate products causing reduced physiological doses, there is a minimum risk for adverse events. The
mineralization of bone matrix, the latter effect can result in rickets in excess of vitamin D is stored in body fat and transforms itself according
children and osteomalacia in adults. Vitamin D, by increasing calcium to the daily physiological requirements [13]. When 1,25-(OH)2-D3
absorption, prevents hyperparathyroidism and benefits the development (calcitriol) is administered, a direct pharmacological effect is observed
of optimal bone mass and proper bone matrix mineralization. Both and may cause hypercalcemia, with a subsequent risk of hypercalciuria
factors are responsible for optimizing the mechanical strength of bone and renal lithiasis [68,77,78]. Alfacalcidiol (1-α-(OH)-D3) is a synthetic
[4,27,52]. In children, an adequate consumption of vitamin D is related inactive pro-hormone that must be hydroxylated in the liver to
Rheumatol Orthop Med, 2020 doi: 10.15761/ROM.1000171 Volume 5: 4-9Vidal M (2020) The importance of vitamin D
transform into 1,25-(OH)2-D3. Just as calcitriol, this form surpasses the ergocalciferol to increase serum concentrations of 25-(OH)-D; but also,
vitamin D synthesis main control mechanism, which is hydroxylation the best route of administration of this vitamin is oral [89].
in position 1 in the kidney, thus its administration must be considered
a pharmacological treatment. However, when calcitriol or alfacalcidiol What level of 25-OH-D should we reach?
are used, the problem of filling body deposits with vitamin D is not The purpose of vitamin D supplementation is to maximize
solved [79-81]. calcium absorption and to reduce deleterious effects of a PTH rise
Calcitriol, alfacalcidiol and other analogs are used in the on the bone. Supplementation with vitamin D may also reduce the
management of patients with chronic kidney diseases, whose kidney risk of fractures, improve bone mass and optimize the response to
hydroxylation is diminished; and also have shown to be useful when antiresorptive or anabolic agents [4,74,75,90]. However, what is the
surpassing the regulatory mechanism is needed, like with vitamin D optimal level of 25-(OH)-D to be reached in the serum and with which
resistant rickets [81-83]. However, it is not advisable to use calcitriol or of these objectives can be achieved? From a biochemical point of view,
alfacalcidiol to correct a vitamin D deficiency in all patients, since a direct the maximal suppression of the circulating PTH concentrations, and
pharmacological effect would be applied, which is beyond the control of maximization of calcium absorption are considered the most important
the regulatory mechanisms [79,82]. Both vitamin D3 (cholecalciferol) endpoints [91,92]. Some studies suggest that in subjects with a serum
and vitamin D2 (ergocalciferol) are effective in correcting and keeping concentration of 25-(OH)-D between 30-40 ng/ml, the connection
serum levels of 25-(OH)-D [27], but they are not bioequivalents [84]. between 25-(OH)-D and serum PTH, becomes inversely proportional
Since 1930, Hess suggested that the activity of cod liver oil, which significantly; in a way that with serum values of 25-(OH)-D above this
contains vitamin D3, was different from the biological value of vitamin level, concentration PTH is minimized [92-95]. Studies have determined
D2, which was obtained from UV irradiation of ergot of rye or from that with levels of 25-(OH)-D above 34.6 ng/ml (86.4 nmol/L), calcium
lipid yeast extract, called “viosterol”. This was then the patented and absorption is increased by 45%-65% compared to levels of 20 ng/ml (50
licensed form of synthesis of vitamin D2 by pharmaceutical companies nmol/L) [94,96].
at that time [85]. When the efficacy of cholecalciferol and ergocalciferol Using the value of at least 30 ng/ml (75 nmol/L) as cut-off point
is compared in elevating the serum levels of 25-(OH)-D, the increase is and comparing it with the most important clinical objective, incident
70% greater with cholecalciferol in relation to ergosterol [86], and a 2.5- fractures, in studies with vitamin D supplement increased the serum
fold higher dose of ergocalciferol is needed to obtain a similar plasma concentrations of 25-(OH)-D to values between 28.4 to 39.6 ng/ml (71
concentration of 25-(OH)-D than that observed with cholecalciferol to 99 nmol/L), there was a significant reduction in fracture rate; while
[87]. Additionally, ergocalciferol is less stable than cholecalciferol [88]. studies with the serum concentrations of 25-(OH)-D were increased
Armas evaluated the efficacy in elevating the concentrations of to values between 21.6 to 24.8 ng/ml (54–62 nmol/L), there was no
25-(OH)-D with single doses of cholecalciferol or ergocalciferol orally, evidence of reduction in fracture risk [96]. The IOF position statement
for 28 days. Both forms of vitamin D were associated with a rapid on vitamin D for older adults recommends that the estimated average
elevation of 25-(OH)-D in the plasma during the first 3 days; however, vitamin D requirement to reach a serum 25-OH-D level of 30 ng/ml
with ergocalciferol, the maximum plasma concentration is reached on (75 nmol/L) is 800 to 1,000 IU/day, but considerably higher doses or a
the 14th day of administration and, subsequently, on the 28th day, it falls repletion dose would be needed to reach this level in almost all older
below the baseline value. With cholecalciferol the values of 25-(OH)-D adults [47]. The next question often asked is for how long is it required
in the plasma also reach their maximum concentration on the 14th day to supplement the recommended daily dose of vitamin D (at least 800
after its administration, however, they remained elevated above the IU daily) to reach this value? A recent study evaluated the effects of
baseline value at 28º day. The area under the curve of both forms of a daily dose of 800 IU in a group of African American women, this
vitamin D, showed that cholecalciferol is three times more potent than study had a 25-(OH)-D baseline value of 18.8 ng/ml (46.9 nmol/L),
ergocalciferol [84]. after treatment this value increased significantly by the third month
to 28.6 ng/ml (71.4 nmol/L), and by the 24th month, the value was of
A meta-analysis that compares the efficacy of vitamin D2 and 26.4 ng/ml (65.9 nmol/L). At 24th month of the study, the vitamin D
vitamin D3 in raising serum 25-OH-D levels concludes that vitamin dose was increased to 2,000 IU daily; and the levels that were at 26.4
D3 is more efficacious at raising serum 25-(OH)-D concentrations than
ng/ml (65.9 nmol/L), increased to 34.9 ng/ml (87.2 nmol/L) [97]. This
vitamin D2 (P= 0.001), and favor the supplement with cholecalciferol
work had several implications. In this group of patients with vitamin
over ergocalciferol [76]. Finally, there are published recommendations
D deficiency, the administration of the recommended daily dose
for supplementation of vitamin D. A recent study analyzes the efficiency
(800 IU daily) and maintained at the same dose for two years did not
of a single mega dose of 300,000 IU of cholecalciferol or ergocalciferol,
significantly increased the 25-(OH)-D values to a level considered as
administered orally and intramuscular, monitoring for 60 days in
adequate. Therefore, administration of the dose equivalent to the daily
women who lived in nursing homes. The authors found a significant rise
requirement (800 IU) to patients with a vitamin D deficiency does
of 25-(OH)-D over baseline only when cholecalciferol or ergocalciferol
not permit them to achieve the desired serum levels, nor correct the
were administrated orally; reaching the desired or ideal value of 32 ng/
deficiency [97].
ml (80 nmol/L) of 25-(OH)-D in a rapid and consistent manner [89].
With the intramuscular application of both forms of vitamin D, there In another study composed mostly of Caucasian women, 40%
was a slow, continuous and progressive rise of 25-(OH)-D levels during of subjects had serum 25-(OH)-D levelsVidal M (2020) The importance of vitamin D
for osteoporosis, included a population of 1,536 postmenopausal antiresorptive medications or with severe and symptomatic deficiency,
women, who received alendronate, calcitonin, etidronate, raloxifene, a rapid correction can be achieved with higher doses of vitamin D [58].
risedronate, or teriparatide, for a minimum of three months, to prevent Loading doses of 300,000 IU and even ≥100,000 for some guidelines
or to treat osteoporosis, in addition to calcium and vitamin D. The are not recommended, because high intermittent loading doses have
investigators reported an average serum concentration of 25-(OH)-D shown a paradoxical increased in falls and fractures [46]. Indeed, a
of 30.4 ± 13.2 ng/ml (75.8 ± 32.9 nmol/L); but 52% of the patients had number of studies using bolus dosing of 300,000–600,000 IU of vitamin
suboptimal levels of 25-(OH)-D (defined as 75%). Patients values are between 20 and 30 ng/ml they recommend administering the
were classified in two groups that included vitamin D deficiency loading dose of 50,000 only for 4 weeks [105-107]. Another proposed
(n=514) or vitamin D sufficiency (n=1,001). The investigators found alternative is to administer a total dose of approximately 300,000 IU
a significantly greater increase in bone mineral density in the lumbar during 6-10 weeks, daily or weekly [58]. Finally, it is up to the clinician
spine, femoral neck, and total hip in women with sufficient levels of to choose the dosing regimen that is convenient for correcting vitamin
vitamin D. The adjusted incidence of clinical fractures was 77% higher D deficiency in any particular patient and consider that the maintenance
in women with a deficiency of vitamin D (25-(OH)-D < 20 ng/ml (50 dose should be continued indefinitely.
nmol/L) (RO 1,77; IC 95%: 1,20-2,59 p=0,004) [73]. These studies
For cut-off points to determine the status of vitamin D and the
emphasize the importance of correcting vitamin D deficiency in
population group to which these guidelines are directed (eg adults,
patients with osteoporosis to obtain an adequate response to treatment.
postmenopausal women) please review the specific references
However, administering the dose equivalent to the daily requirement,
for a person with insufficiency or deficiency of this vitamin, does not US ES (US Endocrine Society): Vitamin D deficiency is defined as
always correct the deficiency and does not improve vitamin D reserves. a 25-(OH)-D below 20 ng/ml (50 nmol/L), and vitamin D insufficiency
as a 25-(OH)-D of 21–29 ng/ml (525–725 nmol/L).
Treatment of vitamin D deficiency
To correct vitamin D deficiency, doses higher than the daily Table 2. Treatment for vitamin D deficiency in adults. For cut-off points to determine the
requirement are needed and treatment should be aimed at normalizing status of vitamin D and the population group to which these guidelines are directed (eg
adults, postmenopausal women) please review the specific references.
serum 25-(OH)-D values and replenishing vitamin D stores. After
correcting the deficiency, the daily requirement must be continued. The Institution Recommendation
form of vitamin D to be chosen, the dose and the treatment schedule may 50,000 IU of vitamin D once a week for 8 weeks or 6000 IU/day
US ES [27] of vitamin D
vary according to the severity of the deficiency, age, and body weight Maintenance doses: 1,500-2,000 UI/d
[99]. It should also be taken into account that levels of 25-(OH)-D in For rapid correction: A fixed loading regimen to provide a total
response to vitamin D intake appear to be quite variable; some people of ≈ 300 000 IU of vitamin D, given either as separate weekly or
remain deficient, while others respond with high and undesirable levels NOS [58] daily doses over 6-10 weeks2
of 25-(OH)-D following the same recommendations [100]. Maintenance doses: 800-2,000 IU/d (occasionally up to 4,000 IU
daily), given either daily or intermittently at higher doses
Vitamin D has a long half-life and supplements can be prescribed EMAS Position Women with serum 25-(OH)-D levels < 20 ng/ml: 4000-10,000
for longer intervals than daily administration. Adherence to treatment Statement [106] IU/day to achieve adequate levels (>30 ng/ml)
is important; and since different daily, weekly or monthly schedules 50,000 IU of vitamin D once a week for 8 weeks or daily dose of
5000 IU of vitamin D for 8 weeks
have shown efficacy in correcting vitamin D deficiency this aspect Italian AME [99]
Maintenance doses: 50,000 IU twice a month; or a daily dose of
should be considered to improve adherence [101]. Supplementation 2000 IU
with vitamin D increases serum 25-OH-D levels, but some special Central Europe
1,000-10,000 IU/day (≈ 50,000 IU/week), depending on the
situations require higher doses of vitamin D as in obese patients or in Practical guidelines
patient’s age and body weight from 1-3 months
those subjects who concomitantly receive medications that interact [103]
with the metabolism of vitamin D (E.g. Anticonvulsive medications, 50,000 IU once weekly for 8 weeks or 6000 IU/day3
Saudi Arabia expert
Maintenance doses: 1000-2000 IU/day once serum 25-(OH)-D
glucocorticoids, cholestyramine, ketoconazole), a 2 to 3 times higher consensus [107]
level is above 30 ng/ml
doses are often required to treat and prevent vitamin D deficiency in 25-(OH)-DVidal M (2020) The importance of vitamin D
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